Amino-tetralin derivatives as muscarinic receptor antagonists

ABSTRACT

This invention relates to compounds which are generally muscarinic M2/M3 receptor antagonists and which are represented by Formula I:                    
     wherein R 1 , R 2 , R 3  and R 4  are as defined in the specification, or individual isomers, racemic or non-racemic mixtures of isomers, or acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use and preparation as therapeutic drugs.

CROSS-REFERENCE

This application claims the benefit of priority of U.S. ProvisionalPatent Application Serial No. 60/336,675, filed Dec. 3, 2001, which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to amino-tetralin derivatives, associatedacceptable salts, or hydrates thereof, and associated compositions andmethods for use as M2/M3 selective muscarinic receptor antagonists.

BACKGROUND OF THE INVENTION

Acetylcholine (Ach) is the principal transmitter of the parasympatheticnervous system. The physiological actions of Ach are mediated byactivation of either nicotinic or muscarinic receptors. Both of thesereceptor classes are heterogeneous: e.g., the muscarinic receptor familycomprises five subtypes (M₁, M₂, M₃, M₄, and M₅) each encoded bydistinct genes and possessing unique pharmacology and distribution.

Almost all smooth muscle tissues express both muscarinic M2 and M3receptors, both of which have a functional role. M2 receptors outnumberM3 receptors by a proportion of approximately 4 to 1. Generally, M3receptors mediate the direct contractile effects of acetylcholine in thevast majority of smooth muscle tissues. M2 receptors, on the other hand,cause smooth muscle contraction indirectly by inhibiting sympathetically(β-adrenoreceptor)-mediated relaxation.

Compounds that act as antagonists of muscarinic receptors have been usedto treat several disease states associated with improper smooth musclefunction, as well as in the treatment of cognitive and neurodegenerativedisorders such as Alzheimer's disease. Until recently, most of thesecompounds have been non-selective for the various muscarinic receptorsubtypes, leading to unpleasant anti-cholinergic side-effects such asdry mouth, constipation, blurred vision, or tachycardia. The most commonof these side-effects is dry-mouth resulting from muscarinic receptorblockade in the salivary gland. Recently developed M2 or M3 specificantagonists have been shown to have reduced side effects. Evidencesuggests that mechanistically, concurrent blockade of M2 and M3receptors could be therapeutically effective in the treatment of diseasestates associated with smooth muscle disorders.

Additionally, muscarinic receptor antagonists are front-line therapy asbronchodilators in chronic obstructive pulmonary disease (COPD). It isthought that the efficacy of this class of molecules is mediated throughantagonism of the natural transmitter (acetylcholine) at M3 receptors onairway smooth muscle and there may be additional benefit in COPD throughinhibition of mucus secretion which may also be mediated through M3receptors. The current standard antimuscarinic for the treatment of COPDis ipratropium (Atrovent) which is administered by aerosol 4 times perday. More recently tiotropium (Spiriva) has been developed byBoehringer-lngelheim as a second-generation muscarinic antagonist and isexpected to be launched in 2002 (in collaboration with Pfizer).Tiotropium is also given by aerosol but has a slow off-rate from the M3receptor and, as a result, causes a prolonged bronchodilatation.Tiotropium will be given once per day. Although tiotropium has highaffinity for all muscarinic receptor subtypes, it is a quatemaryammonium compound which is poorly absorbed.

Few M2/M3 selective antagonists have been developed. The presentinvention fills this need by providing these types of antagonists usefulin the treatment of disease states associated with improper smoothmuscle function and respiratory disorders.

SUMMARY OF THE INVENTION

This invention relates to compounds comprising Formula I:

wherein:

R¹ is (C₁₋₆)alkyl;

R² is halogen or —OR′;

R³ is hydrogen or —OR′;

R′ is hydrogen, (C₁₋₆)alkyl, or SO₂R″;

R″ is (C₁₋₆)alkyl, haloalkyl, aryl or heteroaryl, wherein said aryl orheteroaryl groups are optionally substituted with a group selected from(C₁₋₆)alkyl, halo, haloalkyl, cyano, nitro, alkylsulfonyl, andalkylsulfonylamino,

R⁴ is (C₁₋₆)alkyl, aryl, heterocyclyl, or heteroaryl, wherein said aryl,heterocyclyl or heteroaryl groups are optionally substituted with agroup selected from (C₁₋₆)alkyl, halo, haloalkyl, (C₁₋₆)alkoxy, cyano,amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl,urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl,alkoxycarbonyl, heterocyclyl and heteroaryl, or —NR⁵R⁶; and

R⁵ and R⁶ are independently of each other hydrogen, (C₁₋₆)alkyl, aryl orheterocyclyl; wherein said aryl or heterocyclyl groups are optionallysubstituted with (C₁₋₆)alkyl, halo, haloalkyl, cyano, (C₁₋₆)alkoxy, andalkylsulfonyl,

or prodrugs, individual isomers, racemic or non-racemic mixtures ofisomers, or salts or solvates thereof.

In preferred embodiments R² is (C₁₋₆)alkoxy, hydroxy or —OSO₂R″ whereinR″ is (C₁₋₆)alkyl, haloalkyl, aryl or heteroaryl, and R³ is hydrogen or(C₁₋₆)alkyl; in another preferred embodiment R² is (C₁₋₆)alkoxy and R³is hydrogen, and in another preferred embodiment R² and R³ are(C₁₋₆)alkoxy.

In another preferred embodiment R⁴ is (C₁₋₆)alkyl, and within thisembodiment other preferred group of compounds is that wherein R¹ isethyl or propyl.

In another preferred embodiment R⁴ is an aryl group; and in anotherpreferred embodiment R⁴ is phenyl optionally substituted with a groupselected from (C₁₋₆)alkyl, halo, haloalkyl, (C₁₋₆)alkoxy, cyano, amino,mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl, urea,alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl,alkoxycarbonyl, heterocyclyl and heteroaryl, and within this embodimentother preferred group of compounds is that wherein R¹ is ethyl orpropyl. Another preferred group of compounds is that wherein R² is —OR′,and R³ is —OR′ or hydrogen.

In another preferred embodiment R⁴ is a heteroaryl group; and in anotherpreferred embodiment R⁴ is selected from furanyl, thiophenyl,isooxazolyl, oxazolyl, imidazolyl, and pyrazolyl, all optionallysubstituted with one or two (C₁₋₆) alkyl, and within this embodimentanother preferred group of compounds is that wherein R¹ is ethyl orpropyl, and another preferred group of compounds is that wherein R² is—OR′, and R³ is —OR′ or hydrogen.

In another preferred embodiment R⁴ is a heterocyclyl group; and inanother preferred embodiment R⁴ is piperidinyl, pyrrolidinyl,morpholinyl, piperazinyl, diazepanyl, all optionally substituted withone or two (C₁₋₆)alkyl or alkylcarbonyl groups, and within thisembodiment another preferred group of compounds is that wherein R¹ isethyl or propyl, and another preferred group of compounds is thatwherein R² is —OR′, and R³ is —OR′ or hydrogen.

In another preferred embodiment R⁴ is —NR⁵R⁶, and R⁵ is (C₁₋₆)alkyl andR⁶ is hydrogen or (C₁₋₆)alkyl; and in another preferred embodiment R⁴ is—NR⁵R⁶, R⁵ is heterocyclyl and R⁶ is hydrogen, and within thisembodiment another preferred group of compounds is that wherein R¹ isethyl or propyl, and another preferred group of compounds is thatwherein R² is —OR′, and R³ is —OR′ or hydrogen.

In another aspect, the invention relates to pharmaceutical compositionscontaining a therapeutically effective amount of at least one compoundof Formula I, or individual isomers, racemic or non-racemic mixtures ofisomers and salts or solvates thereof, in admixture with at least onesuitable carrier.

In another aspect, this invention relates to a method of treatment of adisease in a mammal treatable by administration of at least one compoundof Formula I, having selective activity for the M2 and M3 muscarinicreceptors, in particular a method of treatment in a subject having adisease state comprising smooth muscle disorders; preferablygenitourinary tract disorders, respiratory tract disorders,gastrointestinal tract disorders; more preferably genitourinary tractdisorders such as overactive bladder or detrusor hyperactivity and itssymptoms, such as the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity and the like; and the symptoms usually manifestedin detrusor hyperreflexia (neurogenic bladder), in conditions such asoutlet obstruction, outlet insufficiency, pelvic hypersensitivity, or inidiopathic conditions such as detrusor instability, and the like. Inanother preferred embodiment, the disease comprises respiratory tractdisorders such as allergies and asthma. In another preferred embodiment,the disease state comprises gastrointestinal disorders.

In another aspect, the invention relates to a process for preparing acompound of Formula I, which process comprises reacting a compoundhaving a general formula d:

wherein R¹, R², and R³ are as described in the summary of the invention,with a compound of formula R⁴C(O)L, wherein L is a leaving group and R⁴is as described in the summary of the invention, to give a compound ofFormula I:

wherein R¹, R², R³ and R⁴ are as described in the summary of theinvention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonradical, having from one to six carbon atoms inclusive, unless otherwiseindicated. Examples of alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, 1-ethylpropyl, sec-butyl, tert-butyl,n-butyl, n-pentyl, n-hexyl, and the like. “Aryl” means the monovalentaromatic carbocyclic radical consisting of one individual ring, or oneor more fused rings in which at least one ring is aromatic in nature,which can optionally be substituted with one or more, preferably one ortwo, substituents selected from hydroxy, cyano, (C₁₋₆)alkyl,(C₁₋₆)alkoxy, haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl,nitro, cyano, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,alkylcarbonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,arylaminocarbonyl, alkylcarbonylamino, alkylaminocarbonyl,arylcarbonylamino, heterocyclyl, heteroaryl, and urea, unless otherwiseindicated. Alternatively two adjacent atoms of the aryl ring may besubstituted with a methylenedioxy or ethylenedioxy group. Examples ofaryl radicals include, but are not limited to, phenyl, naphthyl,biphenyl, indanyl, anthraquinolyl, tert-butyl-phenyl, 1,3-benzodioxolyl,o-tolyl, trifluoromethylphenyl, methanesulfonylphenyl, ureaphenyl,pyrrolydinylphenyl, tetrazolylphenyl, and the like.

“Heteroaryl” means the monovalent aromatic cyclic radical having one ormore rings, preferably one to three rings, of four to eight atoms perring, incorporating one or more heteroatoms, preferably one or two,within the ring (chosen from nitrogen, oxygen, or sulfur), which canoptionally be substituted with one or more, preferably one or twosubstituents selected from hydroxy, cyano, (C₁₋₆)alkyl, (C₁₋₆)alkoxy,lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro,cyano, alkoxycarbonyl, amino, alkylamino, alkylcarbonyl, alkylsulfonyl,arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and urea, unless otherwiseindicated. Examples of heteroaryl radicals include, but are not limitedto, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazinyl, pyrazolyl,tetrazolyl, thienyl, furanyl, pyridinyl, quinolinyl, isoquinolinyl,benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzopyranyl, indazolyl, indolyl,isoindolyl, quinolinyl, isoquinolinyl, naphthyridinyl,benezenesulfonyl-thiophenyl, and the like.

“Heterocyclyl” means the monovalent saturated cyclic radical, consistingof one or more rings, preferably one to two rings, of three to eightatoms per ring, incorporating one or more ring heteroatoms (chosen fromN, O or S(O)₀₋₂), and which can optionally be substituted with one ormore, preferably one or two substituents selected from hydroxy, oxo,cyano, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, haloalkoxy, alkylthio, halo,haloalkyl, hydroxyalkyl, nitro, cyano, alkoxycarbonyl, amino,alkylamino, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, arylcarbonyl,alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and urea unless otherwiseindicated. Examples of heterocyclic radicals include, but are notlimited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydropyranyl, thiomorpholinyl, 2-oxo-pyrrolidinyl,3,5-dimethyl-piperazinyl, 4-methylpiperazin-1-yl,1-methyl-piperidin-4-yl and the like.

“Haloalkyl” means the alkyl radical as defined herein substituted in anyposition with one or more halogen atoms as defined herein. Examples ofhaloalkyl radicals include, but are not limited to, 1,2-difluoropropyl,1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2,2-trichloroethyl, and the like.

“Halogen” means the radical fluoro, bromo, chloro, and/or iodo.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optional bond” means that the bondmay or may not be present, and that the description includes single,double, or triple bonds.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under alkylating conditions. Examples of leavinggroups include, but are not limited to, halogen, alkane- orarylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive oxygen atoms present in thereactants. Acceptable protective groups for alcoholic or phenolichydroxyl groups, which may be removed successively and selectivelyincludes groups protected as acetates, haloalkyl carbonates, benzylethers, alkylsilyl ethers, heterocyclyl ethers, and methyl or alkylethers, and the like. Protective or blocking groups for carboxyl groupsare similar to those described for hydroxyl groups, preferablytert-butyl, benzyl or methyl esters. Examples of protecting groups canbe found in T. W. Greene et al., Protective Groups in Organic Chemistry,(J. Wiley, 2^(nd) ed. 1991) and Harrison et al., Compendium of SyntheticOrganic Methods, Vols. 1-8 (J. Wiley and Sons 1971-1996).

“Amino-protecting group” means the protecting group that refers to thoseorganic groups intended to protect the nitrogen atom against undesirablereactions during synthetic procedures and includes, but is not limitedto, benzyl (Bnz), benzyloxycarbonyl (carbobenzyloxy, Cbz),p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like. It ispreferred to use either Boc or Cbz as the amino-protecting group becauseof the relative ease of removal, for example by mild acids in the caseof Boc, e.g., trifluoroacetic acid or hydrochloric acid in ethylacetate; or by catalytic hydrogenation in the case of Cbz.

“Deprotection” or “deprotecting” means the process by which a protectivegroup is removed after the selective reaction is completed. Certainprotective groups may be preferred over others due to their convenienceor relative ease of removal. Deprotecting reagents for protectedhydroxyl or carboxyl groups include potassium or sodium carbonates,lithium hydroxide in alcoholic solutions, zinc in methanol, acetic acid,trifluoroacetic acid, palladium catalysts, or boron tribromide, and thelike.

“Isomerism” means compounds that have identical molecular formulae butthat differ in the nature or the sequence of bonding of their atoms orin the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

“Chiral isomer” means a compound with one chiral center. It has twoenantiomeric forms of opposite chirality and may exist either as anindividual enantiomer or as a mixture of enantiomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”. A compound that has more thanone chiral center has 2^(n−1) enantiomeric pairs, where n is the numberof chiral centers. Compounds with more than one chiral center may existas either an individual diastereomer or as a mixture of diastereomers,termed a “diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al. 1966, Angew. Chem. Inter. Edit., 5, 385; errata 511; Cahnet al. 1966, Angew. Chem., 78, 413; Cahn and Ingold 1951, J. Chem. Soc.(London), 612; Cahn et al. 1956, Experientia. 12, 81; Cahn, J. 1964,Chem.Educ., 41, 116).

“Geometric Isomers” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

“Atropic isomers” means the isomers owing their existence to restrictedrotation caused by hindrance of rotation of large groups about a centralbond.

“Substantially pure” means at least about 80 mole percent, morepreferably at least about 90 mole percent, and most preferably at leastabout 95 mole percent of the desired enantiomer or stereoisomer ispresent.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Acceptable salts” of a compound means salts that are pharmaceuticallyacceptable, as defined herein, and that possess the desiredpharmacological activity of the parent compound. Such salts include:

(1) acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid,benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glutamic acid, glycolic acid, hydroxynaphthoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonicacid, propionic acid, salicylic acid, succinic acid,dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid,trimethylacetic acid, trifluoroacetic acid, and the like; or

(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicor inorganic base. Acceptable organic bases include diethanolamine,ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred acceptable salts are the salts formed from hydrochloricacid, trifluoroacetic acid, dibenzoyl-L-tartaric acid, and phosphoricacid.

It should be understood that all references to acceptable salts includesolvent addition forms (solvates) or crystal forms (polymorphs) asdefined herein, of the same acid addition salt.

“Crystal forms” (or polymorphs) means crystal structures in which acompound can crystallize in different crystal packing arrangements, allof which have the same elemental composition. Different crystal formsusually have different X-ray diffraction patterns, infrared spectra,melting points, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate.

“Solvates” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Prodrug” or “pro-drug” means a pharmacologically inactive form of acompound which must be metabolized in vivo, e.g., by biological fluidsor enzymes, by a subject after administration into a pharmacologicallyactive form of the compound in order to produce the desiredpharmacological effect. Prodrugs of a compound of Formula I are preparedby modifying one or more functional group(s) present in the compound ofFormula I in such a way that the modification(s) may be cleaved in vivoto release the parent compound. Prodrugs include compounds of Formula Iwherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in acompound of Formula I is bonded to any group that may be cleaved in vivoto regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonylgroup respectively. Examples of prodrugs include, but are not limitedto, esters (e.g. acetate, dialkylaminoacetates, formates, phosphates,sulfates and benzoate derivatives) and carbamates of hydroxy functionalgroups (e.g. N,N-dimethylcarbonyl), esters of carboxyl functional groups(e.g. ethyl esters, morpholinoethanol esters), N-acyl derivatives (e.g.N-acetyl), N-Mannich bases, Schiff bases and enaminones of aminofunctional groups, oximes, acetals, ketals, and enol esters of ketonesand aldehyde functional groups in compounds of Formula I, and the like.

The prodrug can be metabolized before absorption, during absorption,after absorption, or at a specific site. Although metabolism occurs formany compounds primarily in the liver, almost all other tissues andorgans, especially the lung, are able to carry out varying degrees ofmetabolism. Prodrug forms of compounds may be utilized, for example, toimprove bioavailability, improve subject acceptability such as bymasking or reducing unpleasant characteristics such as bitter taste orgastrointestinal irritability, alter solubility such as for intravenoususe, provide for prolonged or sustained release or delivery, improveease of formulation, or provide site-specific delivery of the compound.Reference to a compound herein includes prodrug forms of a compound.Prodrugs are described in The Organic Chemistry of Drug Design and DrugAction, by Richard B. Silverman, Academic Press, San Diego, 1992.Chapter 8: “Prodrugs and Drug delivery Systems” pp.352-401; Design ofProdrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985;Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed.by E. B. Roche, American Pharmaceutical Association, Washington, 1977;and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press,Oxford, 1980.

“Subject” means mammals and non-mammals. Mammals means any member of theMammalia class including, but not limited to, humans, non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compoundand disease state being treated, the severity of the disease treated,the age and relative health of the subject, the route and form ofadministration, the judgement of the attending medical or veterinarypractitioner, and other factors.

“Pharmacological effect” as used herein encompasses effects produced inthe subject that achieve the intended purpose of a therapy. In onepreferred embodiment, a pharmacological effect means that primaryindications of the subject being treated are prevented, alleviated, orreduced. For example, a pharmacological effect would be one that resultsin the prevention, alleviation or reduction of primary indications in atreated subject. In another preferred embodiment, a pharmacologicaleffect means that disorders or symptoms of the primary indications ofthe subject being treated are prevented, alleviated, or reduced. Forexample, a pharmacological effect would be one that results in theprevention or reduction of primary indications in a treated subject.

“Disease state” means any disease, condition, symptom, or indication.

“Treating” or “treatment” of a disease state includes:

(1) preventing the disease state, i.e. causing the clinical symptoms ofthe disease state not to develop in a subject that may be exposed to orpredisposed to the disease state, but does not yet experience or displaysymptoms of the disease state;

(2) inhibiting the disease state, i.e., arresting the development of thedisease state or its clinical symptoms; or

(3) relieving the disease state, i.e., causing temporary or permanentregression of the disease state or its clinical symptoms.

“Antagonist” means a molecule such as a compound, a drug, an enzymeinhibitor, or a hormone, that diminishes or prevents the action ofanother molecule or receptor site.

“Disorders of the urinary tract” or “uropathy” used interchangeably with“symptoms of the urinary tract” means the pathologic changes in theurinary tract. Symptoms of the urinary tract include overactive bladder(also known as detrusor hyperactivity), outlet obstruction, outletinsufficiency, and pelvic hypersensitivity.

“Overactive bladder” or “Detrusor hyperactivity” includes, but is notlimited to, the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity, and the like; and the symptoms usuallymanifested in detrusor hyperreflexia (neurogenic bladder), in conditionssuch as outlet obstruction, outlet insufficency, pelvichypersensitivity, or in idiopathic conditions such as detrusorinstability, and the like.

“Outlet obstruction” includes, but is not limited to, benign prostatichypertrophy (BPH), urethral stricture disease, tumors and the like. Itis usually symptomatically manifested as obstructive (low flow rates,difficulty in initiating urination, and the like) or irritative(urgency, suprapubic pain, and the like).

“Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, or mixed incontinence.It is usually symptomatically manifested as stress incontinence.

“Pelvic Hypersensitivity” includes but is not limited to, pelvic pain,interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia,urethritis, orchidalgia, and the like. It is symptomatically manifestedas pain, inflammation or discomfort referred to the pelvic region, andusually includes symptoms of overactive bladder.

Throughout the application the following abbreviations are used with thefollowing meanings:

Bnz benzyl Boc ter-butoxycarbonyl BPH Benign prostatic hypertrophy orbenign prostatic hyperplasia DMF N,N-Dimethylformamide DMSODimethylsulfoxide EDCl 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride EtOAc Ethyl acetate Hal Halogen or halide HOBT1-Hydroxybenzotriazole hydrate Pro Protective group TFA Trifluoroaceticacid TFAA Trifluoroacetic acid anhydride THF Tetrahydrofuran

Nomenclature

The naming and numbering of the compounds of this invention isillustrated below:

In general, the nomenclature used in this Application is based onAUTONOM™, a Beilstein Institute computerized system for the generationof IUPAC systematic nomenclature.

For example a compound of Formula I wherein R¹ is propyl, R² and R³ are—OCH₃, and R⁴ is 4-methyl-piperazin-1-yl is named:{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone.

Preferred Compounds

Among compounds of the present invention set forth in the Summary of theInvention, certain compounds of Formula I, or prodrugs, individualisomers, racemic or non-racemic mixtures of isomers, or acceptable saltsor solvates thereof, are preferred:

R¹ is preferably (C₁₋₆)alkyl, more preferably ethyl and propyl;

R² is preferably halogen or —OR′, more preferably halogen or(C₁₋₆)alkoxy;

R³ is preferably hydrogen or —OR′, more preferably hydrogen or(C₁₋₆)alkoxy;

R′ is preferably hydrogen, (C₁₋₆)alkyl, or —SO₂R″, more preferably(C₁₋₆)alkyl, R″ is preferably (C₁₋₆)alkyl, haloalkyl, aryl orheteroaryl, more preferably aryl or heteroaryl;

R⁴ is —NR⁵R⁶, aryl, heterocyclyl or heteroaryl, more preferablyheterocyclyl or heteroaryl;

R⁵ and R⁶ are independently of each other hydrogen, (C₁₋₆)alkyl, aryl,or heterocylyl, more preferably (C₁₋₆)alkyl or heterocyclyl.

Other preferred compounds of the present invention include theacceptable salts of the compounds of the present invention, wherein theacceptable salts are preferably formed from hydrochloric acid or2,2,2-trifluoroacetic acid.

Exemplary particularly preferred compounds, or prodrugs, individualisomers, racemic or non-racemic mixtures of isomers, or salts orsolvates thereof include:

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone;

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone;

{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone;

{4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone;

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-ethanone;

{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone;

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone,and

{4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone.

GENERAL SYNTHETIC REACTION SCHEMES

Compounds of the present invention may be made by the methods depictedin the illustrative synthetic reaction schemes shown and describedbelow.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser 1991 Reagents for Organic Synthesis; Wiley & Sons: New York,Volumes 1-15; Rodd 1989 Chemistry of Carbon Compounds, Elsevier SciencePublishers, Volumes 1-5 and Supplementals; and 1991 Organic Reactions,Wiley & Sons: New York, Volumes 1-40. The following synthetic reactionschemes are merely illustrative of some methods by which the compoundsof the present invention may be synthesized, and various modificationsto these synthetic reaction schemes may be made and will be suggested toone skilled in the art having referred to the disclosure contained inthis Application.

The starting materials and the intermediates of the synthetic reactionschemes may be isolated and purified if desired using conventionaltechniques, including but not limited to filtration, distillation,crystallization, chromatography, and the like. Such materials may becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably take place at atmospheric pressure over a temperature rangefrom about −78° C. to about 150° C., more preferably from about 0° C. toabout 125° C., and most preferably and conveniently at about room (orambient) temperature, e.g., about 20° C.

SCHEME A

Scheme A, in general describes a method of preparing a compound ofFormula I wherein R¹, R², R³, and R⁴ are as described in the Summary ofthe invention.

A compound of Formula b, wherein Pro is a protective group, cangenerally be prepared by coupling a tetralone of Formula a with aprotected amino piperidine under reductive amination conditions.Suitable reducing conditions include sodium triacetoxyborohydride,sodium cyanoborohydride, titanium isopropoxide and sodiumcyanoborohydride, hydrogen and a metal catalyst and hydrogentransferring agents such as cyclohexene, formic acid and its salts, zincand hydrochloric acid formic acid or borane sulfide followed bytreatment with formic acid. Suitable organic solvents for the reactioninclude dichloromethane, 1,2-dichloroethane, tetrahydrofuran, alcoholsor ethyl acetate, and the like. Preferably the reaction is carried outunder basic conditions with sodium triacetoxyborohydride in1,2-dichloroethane. Reductive amination procedures are described in thechemical literature. For example, J. Org. Chem., 1996, 61, 3849 andTetrahedron Letters, 1996, 37, 3977, describe methods utilizing sodiumtriacetoxyborohydride as a reagent for the reductive amination ofaldehydes with a wide variety of amines. Compound b is further coupledunder reductive amination conditions as described herein, with acarboxaldehyde to generally give a compound of Formula c, wherein R¹ isas described in the summary of the invention , which after deprotectionof the piperidine group under conditions well known in the art asdescribed herein, to give a compound of Formula d, can undergoacylation, with an acid chloride of formula R⁴C(O)L, wherein L is aleaving group and R⁴ is as described in the summary of the invention,under conditions well known in the art, to generally give a compound ofFormula I.

The conventional starting materials of Scheme A are commerciallyavailable or are known to, or can readily be synthesized by those ofordinary skill in the art.

GENERAL UTILITY

Compounds that act as antagonists of muscarinic receptors have been usedto treat several disease states associated with improper smooth musclefunction as well as in the treatment of cognitive and neurodegenerativedisorders such as Alzheimer's disease. Until recently, most of thesecompounds have been non-selective for the various muscarinic receptorsubtypes, leading to unpleasant anti-cholinergic side-effects such asdry mouth, constipation, blurred vision or tachycardia, the most commonof which is dry-mouth that results from muscarinic receptor blockade inthe salivary gland. Recently developed M2 or M3 specific antagonistshave been shown to have reduced side effects. Evidence suggests thatmechanistically, concurrent blockade of M2 and M3 receptors could betherapeutically effective in the treatment of disease states associatedwith smooth muscle disorders, such as genitourinary tract disorders,respiratory tract disorders, gastrointestinal tract disorders, andsmooth muscle disorders.

Genitourinary tract disorders treatable with compounds of this inventionspecifically include overactive bladder or detrusor hyperactivity andits symptoms such as the changes symptomatically manifested as urgency,frequency, reduced bladder capacity, incontinence episodes, and thelike; the changes urodynamically manifested as changes in bladdercapacity, micturition threshold, unstable bladder contractions,sphincteric spasticity, and the like; and the symptoms usuallymanifested in detrusor hyperreflexia (neurogenic bladder), in conditionssuch as outlet obstruction, outlet insufficency, pelvichypersensitivity, or in idiopathic conditions such as detrusorinstability, and the like.

Gastrointestinal tract disorders treatable with compounds of thisinvention specifically include irritable bowel syndrome, diverticulardisease, achalasia, gastrointestinal hypermotility disorders, anddiarrhea. Respiratory tract disorders treatable with compounds of thisinvention specifically include chronic obstructive pulmonary disease,including chronic bronchitis, emphysema, asthma and pulmonary fibrosis.

Compounds with selectivity for the M2 muscarinic receptor have also beenshown to be useful in the treatment of cognitive and neurodegenerativediseases such as for example, Alzheimer's disease, as described in J.Med. Chem. 1993, 36, 3734-3737. U.S. Pat. No. 6,294,554 describesmuscarinic antagonists for the treatment of cognitive disorders.

These and other therapeutic uses are described, for example, in Goodman& Gilman, 1996 The Pharmacological Basis of Therapeutics, ninth edition,McGraw-Hill, New York, Chapter 26:601-616; and Coleman, R. A., 1994,Pharmacological Reviews, 46:205-229.

TESTING

The compounds of this invention are muscarinic receptor antagonists. Themuscarinic receptor affinity of test compounds can be determined by anin vitro receptor binding assay which utilizes a cell membranepreparation from the Chinese hamster ovary cells expressing therecombinant human muscarinic receptors (M₁−M₅), and is described in moredetail in Example 12.

The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated saliva secretion in anesthetizedrats, and is described in more detail in theOxotremorine/Pilocarpine-induced salivation (OIS/PIS) model inanesthetized rats, Example 13.

The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated bladder contraction in anesthetizedrats, and is described in more detail in the inhibition ofvolume-induced contractions assay, Example 14.

The muscarinic antagonist properties of the test compounds can beidentified by an in vivo assay which determines inhibitory activityagainst muscarinic receptor mediated bladder contraction and salivasecretion in anesthetized dogs, and is described in more detail inExample 15.

The muscarinic antagonist properties of the test compounds asanti-bronchoconstriction agents can be identified by an in vivo assay inanesthetized rats as described in more detail in Example 16.

ADMINISTRATION AND PHARMACEUTICAL COMPOSITION

The present invention includes pharmaceutical compositions comprising atleast one compound of the present invention, or a prodrug, an individualisomer, a racemic or non-racemic mixture of isomers or an acceptablesalt, or solvate thereof together with at least one acceptable carrier,and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of the present invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease. In general, compounds of the presentinvention will be administered as pharmaceutical formulations includingthose suitable for oral (including buccal and sub-lingual), rectal,nasal, topical, pulmonary, vaginal, or parenteral (includingintramuscular, intraarterial, intrathecal, subcutaneous and intravenous)administration or in a form suitable for administration by inhalation orinsufflation. The preferred manner of administration is generally oralusing a convenient daily dosage regimen which can be adjusted accordingto the degree of affliction.

A compound or compounds of the present invention, together with one ormore conventional adjuvants, carriers, or diluents, may be placed intothe form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about ten (10) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavoring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets preferably contain fromabout one (1) to about seventy (70) percent of the active compound.Suitable carriers include but are not limited to magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

The compounds of the present invention can be formulated in transdermalor subcutaneous drug delivery devices. These delivery systems areadvantageous when sustained release of the compound is necessary andwhen patient compliance with a treatment regimen is crucial. Compoundsin a transdermal delivery systems are frequently attached to askin-adhesive solid support. The compound of interest can also becombined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington, 1995, The Science and Practice of Pharmacy,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in Examples 5-11.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 1{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

Step 1:

(1-Benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine

To a solution of 7-methoxy-3,4-dihydro-1H-naphthalen-2-one (10 g, 56.7mmol) and 1-benzyl-piperidin-4-ylamine (12.7 mL, 62.4 mmol) indichloroethane (50 mL) under a nitrogen atmosphere was added sodiumtriacetoxyborohydride (30 g, 141.8 mmol, 3.5 eq.) in a single portion.The reaction was stirred at room temperature for 24 h. The reaction wasconcentrated in vacuo and partitioned between EtOAc (100 mL) and 5% aq.KOH (50 mL). The aqueous layer was extracted twice more with EtOAc (2×50mL). The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated to afford a dark oil. This materialwas used directly in Step 2.

Step 2:

(1-Benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine

To a solution of(1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-aminefrom Step 1 and propionaldehyde (4.5 mL, 62.4 mmol) in dichloroethane(200 mL) under a nitrogen atmosphere was added sodiumtriacetoxyborohydride (24 g, 0.113 mol, 2 eq.) in a single portion. Thereaction was stirred at room temperature for 24 h then concentrated invacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH(50 mL). The aqueous phase was extracted twice more with EtOAc (2×30mL). The combined organic layers were dried over MgSO₄, filtered, andconcentrated onto silica (10 g). This was placed on top of a flashcolumn and eluted with 20% hexanes in acetone. The fractions containingproduct were pooled and concentrated to afford(1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amineas a clear oil (6.86 g).

Step 3:

(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine

A solution of(1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine(6.86 g, 14.47 mmol) in absolute ethanol (100 mL) was poured onto aslurry of 20% Palladium hydroxide/C (1.4 g) in absolute ethanol (10 mL).The mixture was placed under a hydrogen atmosphere on the Parr shaker at50 psi for 20 h. The reaction mixture was filtered, and concentrated togive(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(4.2 g).

Step 4a:

{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

To a solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(200 μL of 0.025 M in dichloromethane, 50 μmole) was added 200 μL of0.25 M solution of morpholine 4-carbonyl chloride in dichloromethane and30 μL of DIEA. The solution was allowed to stir for 24 h at 25° C. underN₂. Concentrated in vacuo. The final product was isolated by preparativeRPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1%TFA)) to afford{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone1 (11.9 mg), [M+H]⁺=461.

Step 4b:

Alternatively an acid may be used in the last step as an acylatingagent.1-(4-{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-piperidin-1-yl)-ethanone

To a solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(200 μL of 0.25 M in dimethyl formamide, 50 μmole) was added1-acetylpiperidine-4-carboxylic acid (220 μL of 0.25M in DMF), 300 μL ofEDCI (0.25M in DMF) and 220 uL of HOBT (0.25M in DMF) and 30 μL DIEA.The solution was allowed to stir for 48 h at 25° C. under N₂.Concentrated in vacuo. The final product was isolated by preparativeRPHPLC (YMC Combiprep ODS-A column, 10-90% acetonitrile: water (0.1%TFA)) to afford1-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-piperidin-1-yl)-ethanone2 (5.2 mg ), [M+H]⁺=456.

Similarly following the procedures described above in Example 1 andusing the appropriate acylating compounds in Step 4a or Step 4b,thefollowing compounds were prepared:

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-o-tolyl-methanone3, [M+H]⁺=421;

furan-2-yl-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone4, [M+H]⁺=397;

4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid diethylamide 5, [M+H]⁺=397;

(3,5-dimethyl-isoxazol-4-yl)-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone6, [M+H]⁺=426;

(4-methanesulfonyl-phenyl)-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone7, [M+H]⁺=485;

(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-phenyl)-urea8, [M+H]⁺=465;

1-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-phenyl)-pyrrolidin-2-one9, [M+H]⁺=465;

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-[4-(1H-tetrazol-5-yl)-phenyl]-methanone10, [M+H]⁺=475;

N-(4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carbonyl}-phenyl)-methanesulfonamide11, [M+H]⁺=500;

4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid methylamide 12, [M+H]⁺=360;

4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid (4-trifluoromethyl-phenyl)-amide 13, [M+H]⁺=490;

4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid (3-cyano-phenyl)-amide 14, [M+H]⁺=447;

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-ethanone15, [M+H]⁺=381;

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone16, [M+H]⁺=451;

4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid isopropylamide 17, [M+H]⁺=424;

4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid dimethylamide 18, [M+H]⁺=410;

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone19, [M+H]⁺=450;

{4-[(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(1H-pyrazol-4-yl)-methanone20, [M+H]⁺=433;

((3R,5S)-3,5-Dimethyl-piperazin-1-yl)-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone21, [M+H]⁺=479;

4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid piperidin-4-ylamide 22, [M+H]⁺=465;

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone23, [M+H]⁺=465;

(1H-imidazol-4-yl)-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone24, [M+H]⁺=433;

[1,4]diazepan-1-yl-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-methanone25, [M+H]⁺=465;

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(1-methyl-piperidin-4-yl)-methanone26, [M+H]⁺=395; and

{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-3-yl-methanone 27, [M+H]⁺=450.

Similarly, following the procedure described above in Example 1, butreplacing 7-methoxy-3,4-dihydro-1H-naphthalen-2-one with6,7-dimethoxy-3,4-dihydro-1H-naphthalen-2-one in Step 1 and using theappropriate acylating compounds in Step 4a or Step 4b, the followingcompounds were prepared:

{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone28, [M+H]⁺=480;

{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone29, [M+H]⁺=482;

{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone30, [M+H]⁺=481;

4-[(6,7-Dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid diethylamide 31, [M+H]⁺=468;

{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone32, [M+H]⁺=495; and

{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(1-methyl-piperidin-4-yl)-methanone33, [M+H]⁺=494.

Example 2{4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone

Step 1:

4-(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicAcid Tert-butyl Ester

To a solution of 7-bromo-3,4-dihydro-1H-naphthalen-2-one (500 mg, 2.2mmol) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (445mg, 2.2 mmol) in dichloroethane (50 mL) under a nitrogen atmosphere wasadded sodium triacetoxyborohydride (1.29 g, 5.55 mmol) in a singleportion. The reaction was stirred at room temperature for 24 h. Thereaction was concentrated in vacuo and partitioned between EtOAc (100mL) and 5% aq. KOH (50 mL). The aqueous layer was extracted twice morewith EtOAc (2×50 mL). The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated. Flashchromatography on silica gel eluting with 5% methanol/methylene chlorideafforded4-(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (610 mg).

Step 2:

4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicAcid Tert-butyl Ester

To a solution of4-(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (610 mg, 1.5 mmol) and propionaldehyde (0.1 mL,1.5 mmol) in dichloroethane (20 mL) under a nitrogen atmosphere wasadded sodium triacetoxyborohydride (795 mg, 3.75 mmol) in a singleportion. The reaction was stirred at room temperature for 24 h thenconcentrated in vacuo. The residue was partitioned between EtOAc (75 mL)and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more withEtOAc (2×30 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated onto silica (10 g). This was placed on top ofa flash column and eluted with 20% hexanes in acetone. The fractionscontaining product were pooled and concentrated to afford4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid tert-butyl ester (587 mg).

Step 3:

(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine

To a solution of4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid tert-butyl ester (347 g, 0.77 mmol) in methylene chloride (30 mL)under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). Thereaction was stirred at room temperature for 30 min., and concentratedin vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq.KOH (50 mL). The organic layer was separated, dried over MgSO₄,filtered, and concentrated to afford(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(203 mg).

Step 4:

{4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone

To a solution of the(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(200 μL of 0.25 M in dichloromethane, 50 μmol) was added 220 μL of 0.25M solution of morpholine 4-carbonyl chloride in dichloromethane and 30μL of DIEA. The reaction was stirred at 25° C. for 24 h. Concentrated invacuo. The final product was isolated by preparative RPHPLC (YMCCombiprep ODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-pyrrolidin-1-yl-methanone34 (4.6 mg), [M+H]⁺=562.

Similarly following the procedure described above in Example 2 butreplacing in Step 4 morpholine-4-carbonyl chloride with the appropriatecarbonyl chlorides, the following additional compounds were prepared:

{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone35, [M+H]⁺=499;

{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-methanone36, [M+H]⁺=606;

4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone37, [M+H]⁺=478; and

4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidine-1-carboxylicacid dimethylamide 38, [M+H]⁺=543.

Example 3{4-[((R)-7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone

Step 1:

4-((R)-7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicAcid Tert-butyl Ester

To a solution of (R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride (6.0 g, 28.1 mmol)(prepared as described in the Frenchpatent FR 2,653,765 or available commercially) and4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.7g, 33.7 mmol,1.2 eq.) in dichloroethane (200 mL) under an inert atmosphere was addedsodium triacetoxyborohydride (14.9 g, 70.2 mmol, 2.5 eq). The reactionwas stirred at room temperature for 24 h then concentrated in vacuo. Theresidue was partitioned between EtOAc (200 mL) and 5% KOH (150 mL). Theaqueous layer was extracted twice more with EtOAc (2×75 mL). Thecombined organic layers were dried (MgSO₄), filtered, and concentratedto afford4-((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester as a yellow oil (9.7 g).

Step 2:

((R)-7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine

To a solution of4-((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (9.7g, 23.4 mmol) and propionaldehyde (2.0 mL,28.1 mmol) in dichloroethane (150 mL) under a nitrogen atmosphere wasadded sodium triacetoxyborohydride (10.9 mg, 51.5 mmol) in a singleportion. The reaction was stirred at room temperature for 24 h thenconcentrated in-vacuo. The residue was partitioned between EtOAc (175mL) and 5% aq. KOH (150 mL). The aqueous phase was extracted twice morewith EtOAc (2×30 mL). The combined organic layers were dried over MgSO₄,filtered, and concentrated to afford 10.0 g of the protected amine,which was treated with trifluoroacetic acid as described herein toafford((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(7.0 g).

Step 3:

{4-[((R)-7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone

Under an inert atmosphere was combined((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(7.0 g, 23.14 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butylester (5.3 g, 23.14 mmol), EDCI (4.43 g, 23.14 mmol), HOBT (3.13 g,23.14 mmol), and triethylamine (65 mL, 46.3 mmol) in dichloromethane(140 mL). The mixture was stirred at room temperature for 48 h thenconcentrated in vacuo. The residue was taken-up in EtOAc (150 mL) andwashed with water (100 mL), 1N NaOH (30 mL), and brine (30 mL), thendried (MgSO₄). The solution was filtered, and concentrated. This wasflash chromatographed on silica gel eluting with 20% acetone in hexanesto afford the protected amine (10.0 g), which was deprotected with 10 mLtrifluoroacetic acid as described herein to afford{4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone39 (6.5 g ), [M+H]⁺=450.

Example 4 2-Chloro-benzenesulfonic acid7-{[1-(mornholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylEster

Step 1:

{4-[7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

To an ice-cold solution of(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine(1.0 g, 3.3 mmol) and triethylamine (0.5 ml, 3.6 mmol) under an inertatmosphere was added morpholine-4-carbonyl chloride (0.4 mL, 3.5 mmol)dropwise. The ice bath was removed and the reaction stirred at roomtemperature for 4 h. The methylene chloride was washed 2 times withwater (30 mL), dried (MgSO₄), filtered, and concentrated to afford{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanoneas an oil (1.16 g).

Step 2:

{4-[(7-Hydroxyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone

To a −78° C. solution of{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone(300 mg, 0.72 mmol) and tetrabutylammonium iodide (292 mg, 0.79 mmol) indichloromethane (20 mL) under an inert atmosphere was added borontrichloride (1M, 2.5 mL, 2.5 mmol) dropwise. The reaction was warmed toroom temperature and stirred for 2.5 h. The reaction was quenched byslow addition of water and the organic layer separated and dried(MgSO₄). This was concentrated onto silica (1.5 g) and placed on top ofa flash column. Chromatography eluting with 30% acetone in hexanesafforded{4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone(128 mg).

Step 3:

2-Chloro-benzenesulfonic Acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylEster

To a solution of{4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone(50 μmole in 420 μL DCM) was added 30 μL of DIEA followed by 220 μL of a0.25M solution of 2-chlorobenzenesulfonyl chloride in THF. The solutionwas allowed to stir for 24 h at 25° C. under N₂. Concentrated in vacuo.The final product was isolated by preparative RPHPLC (YMC CombiprepODS-A column, 10-90% acetonitrile: water (0.1% TFA)) to afford2-Chloro-benzenesulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 40 (5.1 mg), [M+H]⁺=690.

Similarly, following the procedure described above in Example 4, butreplacing 2-chlorobenzene sulfonyl chloride with the appropriatesulfonyl chlorides, the following compounds were prepared:

2,5-dichloro-thiophene-3-sulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 41, [M+H]⁺=731;

2-bromo-benzenesulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 42, [M+H]⁺=735;

2-cyano-benzenesulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 43, [M+H]⁺=681; and

3,5-dimethyl-isoxazole-4-sulfonic acid7-{[1-(morpholine-4-carbonyl)-piperidin-4-yl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-ylester 44, [M+H]⁺=675.

Example 5 Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0% Lactose 79.5% Magnesiumstearate  0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Example 6 Composition for Oral Administration

Ingredient % wt./wt. Active ingredient 20.0%  Magnesium stearate 0.5%Crosscarmellose sodium 2.0% Lactose 76.5%  PVP (polyvinylpyrrolidine)1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Example 7 Composition for Oral Administration

Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodiumchloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 g Granulatedsugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.)1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilled water q.s. to 100 mL

The ingredients are mixed to form a suspension for oral administration.

Example 8 Parenteral Formulation (IV)

Ingredient % wt./wt. Active ingredient 0.25 g Sodium Chloride qs to makeisotonic Water for injection to 100 mL

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Example 9 Suppository Formulation

Ingredient % wt./wt. Active ingredient  1.0% Polyethylene glycol 100074.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Example 10 Topical Formulation

Ingredients grams Active compound 0.2-2 Span 60 2 Tween 60 2 Mineral oil5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylatedhydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Example 11 Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 12 Radioligand Binding Studies

The inhibitory activity of compounds of this invention in vitro wasdetermined using a modification of the method described in Hegde, S. S.et al. 1997 Br. J. Pharmacol., 120, 1409-1418.

Cell membranes from Chinese hamster ovary cells expressing therecombinant human muscarinic receptors (m₁−m₅) were employed. The assayswere conducted with the radioligand [³H]N-methyl scopolamine(0.4 nM,specific activity 84 Ci.mmol⁻¹) in a final volume of 0.25 mL Tris-Krebsbuffer. Non-specific binding was defined with 1 μM atropine. Assays wereperformed using scintillation proximity assay technology.Competition-displacement curves were generated using 10 concentrationsof test compounds and were analyzed by iterative curve fitting to a fourparameter logistic equation. pIC₅₀ values (-log of the IC₅₀) wereconverted to pKi values using the Cheng-Prusoff equation.

Compound of this invention were active in this assay. Representativevalues for the M2 and M3 receptor are shown below.

Structure Cpd # Ex m2/ m3

1 1 8.57 8.83

3 1 7.38 7.31

4 1 7.58 7.29

5 1 8.50 8.23

15 1 8.37 8.17

16 1 9.01 8.80

28 1 8.30 7.94

23 1 9.24 8.56

35 2 8.74 9.05

39 3 8.66 9.02

Example 13 Oxotremorine/Pilocarpine-Induced Salivation (OIS/PIS) Modelin Anesthetized Rats.

Female Sprague-Dawley rats (Charles-River, 200-300 g) rats wereanesthetized with urethane (1.5 g/kg, sc) and were tracheotomized. Onefemoral vein was cannulated for drug administration. After a one hourstabilization period, rats were pre-treated with methoctramine (only forOIS) to antagonize M₂ receptor mediated bradycardia. Each animal wasdosed, intravenously, with a single dose of the vehicle or the referencecompound. Ten minutes later, pre-weighed cotton pads were placed in theanimals mouth following which they were dosed with vehicle oroxotremorine (0.1 mg/kg, iv)/pilocarpine (1 mg/kg, iv). Fresh cottonpads were placed at 5 minutes post-oxotremorine/pilocarpine and salivacollected for an additional 5 minutes. The cotton pads (5 and 10-minuteperiod) were then re-weighed to determine the amount of saliva secretedduring the 10-minute period.

All oxotremorine/pilocarpine treated groups were compared using one-wayanalysis of variance. Pair-wise comparisons were made using Dunnett'stest. The ranked data (non-parametric technique) or actual levels of thedata (parametric technique) are applied in the analysis depending uponthe results of the Bartlett's test, which tests homogeneity ofvariances. The vehicle/oxotremorine group and vehicle/pilocarpine wascompared to the vehicle/vehicle group using Wilcox on rank-sum test. Anestimate of the ID₅₀ for each compound with respect to the 10 minuteoverall secretion weight for each animal was obtained. The sigmoidalmodel is in the form of

Resp=min+(max−min)/(1+(dose/ID₅₀)**N)

where ID₅₀ is the dose to achieve half the maximal response, N is thecurvature parameter and max is the max response for the dose responsecurve. The minimum response was fixed at 0 in the model.

Compounds of this invention were active in this assay.

Example 14 Inhibition of Volume-Induced Contractions in Rats

The muscarinic receptor inhibitory activity of compounds of thisinvention in vivo was determined in rats using a modification of themethod described in Hegde, S. S. et al. 1996, Proceedings of the 26thAnnual Meeting of the International Continence Society (August27th-30th), Abstract 126.

Female Sprague-Dawley rats were anesthetized with urethane andinstrumented for intravenous administration of drugs and, in some cases,measurement of arterial pressure, heart rate and intra-bladder pressure.The effect of test compounds on volume-induced bladder contractions wasdetermined in separate groups of animals. Volume-induced reflex bladdercontractions were induced by filling the bladder with saline. The testcompounds were administered intravenously in a cumulative manner at10-minute intervals. Atropine (0.3 mg/kg, iv) was administered at theend of the study as a positive control.

Compounds of this invention were active in this assay.

Example 15 Anti-muscarinic Activity in Anesthetized Dogs

The muscarinic receptor inhibitory activity of compounds of thisinvention in vivo was determined in dogs using a modification of themethod described in Newgreen, D. T. et al. 1996, J. Urol., 155 (Suppl.5), 1156.

Female beagles (Marshall Farms, North Rose, N.Y.) were fasted for 18hours prior to the experiment; water was allowed ad libitum. On the dayof the experiment, dogs were anesthetized and maintained onpentobarbital (36 mg/kg, iv initially, then 5-10 mg/kg, iv formaintenance). Intravenous fluids were also administered to the dog forthe remainder of the experiment. The dogs were artificially ventilated,via an endotracheal tube, with an Harvard respirator (Model 613). Bothfemoral veins and one femoral artery was cannulated for drugadministration and blood pressure measurement, respectively. Bloodpressure was measured with a Gould transducer (Model P23XL) and recordedon a Gould recorder (Model 3400). A sublingual incision was made toexpose the left mandibular duct, which was then cannulated for thecollection of saliva into pre-weighed vials. The left salivary gland wasexposed via a submandibular incision. The chorda-lingual nerve wasisolated and had a bipolar electrode placed on it for stimulation. Testresponses to chorda-lingual nerve stimulation were obtained to confirmproper electrode placement.

After completion of surgery, physostigmine (180 μg/kg/h, iv) (acholinesterase inhibitor) was infused for the remainder of theexperiment. Following a one hour stabilization period, two controlchorda-lingual nerve stimulations were performed at 12 Hz, 10 V, 0.5 msduration (Grass S48). The chorda-lingual nerve was stimulated for 20seconds and 2 minutes, respectively, with a minimum of 10 minuteinterval between each set of stimulations. After two consistent controlresponses were obtained, the vehicle or the reference compound was dosedin a cumulative fashion, 3 minutes prior to each stimulation of thechorda-lingual nerve. Experiments in which consistent salivationresponses could not be obtained were not included in the analysis.Atropine (1.0 mg/kg, iv) was given as a positive control at the end ofthe study.

Mean arterial blood pressure was calculated as Diastolic arterialpressure+(Systolic arterial pressure—Diastolic arterial pressure)/3.Heart rate was derived from the pressure pulse. Saliva was collected inpre-weighed vials and weighed after each collection to determine thevolume of saliva secreted. Inhibition of salivary gland responses wereexpressed as a percent of the effect of atropine (1 mg/kg, iv). ED₅₀Estimation

For % max inhibition salivation, parameter estimation was performedusing a nonlinear mixed model. The method was implemented using PROCNLIN initially and PROC MIXED iteratively. This procedure assumed thefollowing sigmoidal dose-response model:${Response} = {{Min} + \frac{{Max} - {Min}}{1 + 10^{- \frac{({x - \mu})}{\sigma}}}}$

where response=% max inhibition bladder contraction at peak, x=log₁₀dose of treatment and the 4 parameters were: log₁₀ ED50 (μ), maximum andminimum response (Max and Min), and curvature (σ). The minimum wasassumed 0%. This method assumed compound symmetry for the covariancestructure. It was an iterative curve-fitting procedure that accountedfor the dependence between multiple measurements from the same animal,and estimated the desired parameters and their confidence limits byadjusting its error calculations to account for within subjectcorrelation.

Baseline Comparisons

To compare each dose to baseline control for every variable, a two-wayANOVA with main effects of subject and treatment was performed, followedby a pair t-test at each dose level. If the overall treatment effect wasnot significant (p-value>0.05) in ANOVA, a Bonferroni adjustment forp-values was used for the p-value of pair t-test at each dose.

Compounds of this invention were active in this assay.

Example 16 In Vivo Antimuscarinic Activity in Bronchoconstriction Assays

Antagonist activity is assessed against methacholine-inducedbronchoconstriction and bradycardia in the anesthetized rat modelfollowing a procedure similar to that described by Hirose et al, 2001,J. Pharm. Exp. Ther., Vol 297, 790-797. Compounds are givenintravenously, orally or by intratracheal instillation prior tochallenge with intravenous methacholine. Lung resistance and dynamiccompliance are used as indices of bronchoconstriction.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. Compounds of Formula I:

wherein: R¹ is (C₁₋₆)alkyl; R² is halogen or —OR′; R³ is hydrogen or—OR′; R′ is hydrogen, (C₁₋₆)alkyl, or SO₂R″; R″ is (C₁₋₆)alkyl,haloalkyl, aryl or heteroaryl, wherein said aryl or heteroaryl groupsare optionally substituted with a group selected from (C₁6)alkyl, halo,haloalkyl, cyano, nitro, alkylsulfonyl, and alkylsulfonylamino; R⁴ is(i) (C₁₋₆)alkyl, (ii) aryl, heterocyclyl, or heteroaryl, wherein saidaryl, heterocyclyl or heteroaryl groups are optionally substituted witha group selected from (C₁₋₆)alkyl, halo, haloalkyl, (C₁₋₆)alkoxy, cyano,amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl,urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl,alkoxycarbonyl, heterocyclyl and heteroaryl, or (iii) —NR⁵R⁶; and R⁵ andR⁶ are independently of each other hydrogen, (C₁₋₆)alkyl, aryl orheterocyclyl; wherein said aryl or heterocyclyl groups are optionallysubstituted with (C₁₋₆)alkyl, halo, haloalkyl, cyano, (C₁₋₆)alkoxy, andalkylsulfonyl; or an individual isomer, a racemic or non-racemic mixtureof isomers, or an acceptable salt or solvate thereof.
 2. The compound ofclaim 1, wherein R² is (C₁₋₆)alkoxy and R³ is hydrogen.
 3. The compoundof claim 1, wherein R² is (C₁₋₆)alkoxy and R³ is (C₁₋₆)alkoxy.
 4. Thecompound of claim 1, wherein R² is —OSO₂R″ and R³ is hydrogen.
 5. Thecompound of claim 1, wherein R² is hydroxy and R³ is hydrogen.
 6. Thecompound of claim 1, wherein R² is halogen and R³ is hydrogen.
 7. Thecompound of claim 1 wherein R⁴ is (C₁₋₆)alkyl.
 8. The compound of claim7, wherein R¹ is ethyl or propyl.
 9. The compound of claim 8, wherein R²is —OR′, and R³ is —OR′ or hydrogen.
 10. The compound of claim 1,wherein R⁴ is an aryl group.
 11. The compound of claim 10, wherein R⁴ isphenyl optionally substituted with a group selected from (C₁₋₆)alkyl,halo, haloalkyl, (C₁₋₆)alkoxy, cyano, amino, mono- or di alkylamino,nitro, alkylsulfonyl, alkylcarbonyl, urea, alkylcarbonylamino,alkylsulfonylamino, alkylaminosulfonyl, alkoxycarbonyl, heterocyclyl andheteroaryl.
 12. The compound of claim 10, wherein R¹ is ethyl or propyl.13. The compound of claim 11, wherein R¹ is ethyl or propyl.
 14. Thecompound of claim 13, wherein R² is —OR′, and R³ is —OR′ or hydrogen.15. The compound of claim 1, wherein R⁴ is a heteroaryl group.
 16. Thecompound of claim 15, wherein R⁴ is selected from furanyl, thiophenyl,isooxazolyl, oxazolyl, imidazolyl, and pyrazolyl, all optionallysubstituted with one or two (C₁₋₆) alkyl.
 17. The compound of claim 15,wherein R¹ is ethyl or propyl.
 18. The compound of claim 16, wherein R¹is ethyl or propyl.
 19. The compound of claim 18, wherein R² is —OR′,and R³ is —OR′ or hydrogen.
 20. The compound of claim 1, wherein R⁴ is aheterocyclyl group.
 21. The compound of claim 20, wherein R⁴ ispiperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, or diazepanyl, alloptionally substituted with one or two (C₁₋₆)alkyl or alkylcarbonylgroups.
 22. The compound of claim 20, wherein R⁴ is piperidin-4-yl,optionally substituted with one or two (C₁₋₆)alkyl groups oralkylcarbonyl groups.
 23. The compound of claim 20, wherein R⁴ ispiperidin-1-yl, optionally substituted with one or two (C₁₋₆)alkylgroups.
 24. The compound of claim 20, wherein R⁴ is pyrrolidin-1-yl,optionally substituted with one or two (C₁₋₆)alkyl groups.
 25. Thecompound of claim 20, wherein R⁴ is [1,4]-diazepany-1-yl, optionallysubstituted with one or two (C₁₋₆)alkyl groups.
 26. The compound ofclaim 20, wherein R⁴ is piperazin-1-yl, optionally substituted with oneor two (C₁₋₆)alkyl groups.
 27. The compound of claim 20, wherein R⁴ ismorpholinyl, optionally substituted with one or two (C₁₋₆)alkyl groups.28. The compound of claim 20, wherein R¹ is ethyl or propyl.
 29. Thecompound of claim 21, wherein R¹ is ethyl or propyl.
 30. The compound ofclaim 29, wherein R² is —OR′, and R³ is —OR′ or hydrogen.
 31. Thecompound of claim 1, wherein R⁴ is —NR⁵R⁶.
 32. The compound of claim 31,wherein R⁵ is (C₁₋₆)alkyl, and R⁶ is hydrogen or (C₁₋₆)alkyl.
 33. Thecompound of claim 31, wherein R¹ is ethyl or propyl.
 34. The compound ofclaim 33, wherein R² is —OR′, and R³ is —OR′ or hydrogen.
 35. Thecompound of claim 1, comprising:{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone;{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone;{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone;{4-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone;1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-ethanone;{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperazin-1-yl-methanone;{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-(4-methyl-piperazin-1-yl)-methanone;and{4-[(7-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-piperidin-4-yl-methanone.36. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in admixture with an acceptable carrier.37. The pharmaceutical composition of claim 36, wherein the compound issuitable for administration to a subject having a disease state which isalleviated by treatment with a M2/M3 muscarinic receptor antagonist. 38.A method of treating a subject which comprises administering to thesubject with a disease treatable with a M2/M3 muscarinic antagonist atherapeutically effective amount of one or more compounds of claim 1.39. The method of claim 38, wherein the disease state is associated withsmooth muscle disorders comprising diseases of the genitourinary orgastrointestinal tract, or of respiratory states.
 40. The method ofclaim 39, wherein the disease state is associated with the genitourinarytract.
 41. The method of claim 40, wherein the disease state comprisesoveractive bladder, detrusor hyperactivity, urgency, frequency, reducedbladder capacity, incontinence episodes, changes in bladder capacity,micturition threshold, unstable bladder contractions, sphinctericspasticity, outlet obstruction, outlet insufficiency, pelvichypersensitivity, idiopathy conditions, or detursor instability.
 42. Themethod of treatment of claim 39, wherein the disease state comprisesrespiratory states.
 43. The method of treatment of claim 42, wherein thedisease state comprises respiratory states from allergies or asthma. 44.The method of treatment of claim 39, wherein the disease state comprisesgastrointestinal tract disorders.
 45. A process for preparing a compoundas claimed in claim 1 which process comprises reacting a compound havinga general formula d:

wherein R¹, R² and R³ are as described in claim 1, with a compound ofgeneral Formula R⁴C(O)L, wherein L is a leaving group and R⁴ is asdescribed in claim 1, to prepare a compound of Formula I

wherein R¹, R², R³ and R⁴ are as described in claim 1.